The war, the mouse, the protein and the lovers: the curious tale of the search for a common cold vaccine

“Would you like 10 days free holiday and travel expenses paid?”

The advertisements were enticing. They turned up regularly across England for decades. Posters. Newspaper ads. Leaflets. They offered time away in the countryside near Salisbury. Fresh air. Relaxation. Free meals. Not only that, you would be paid for your time. Sound lovely?

Married couples were welcome. Singles were invited, too. There was even the prospect of romance, provided that those interested in courting remain at least thirty feet apart at all times. It wasn’t that the organisers were prudish, they just cared deeply about sneeze range.

Therein lay the catch, after all there’s no such thing as a free lunch, and certainly not ten free lunches in a row. Every holiday maker had a one in three chance of catching a respiratory infection. The organisers would make sure of it. And still people came by the thousands. Their vacation, they were told, would help cure the common cold.

By the end of World War II, while a number of advances were being made in other human viruses such as influenza and polio, still very little was known about the cold. There was strong evidence that it was viral, but that was it.

Rhinoviruses are so pervasive because their viral surfaces vary widely. The proteins that decorate the outside of the viral shell are inconsistent enough that the antibodies your immune system makes to identify and destroy one serotype simply won’t recognise the next one. Immunologists call this a lack of cross-protective immunity.

In addition to evading immune memory, the different surface proteins can tell us something about the history of the virus. Recently a group of scientists in Japan looked at the differences between the surface proteins on the C group of rhinoviruses, and used them to measure how much time has passed as the virus evolved. The strains they analysed could be dated back to between 400 and 900 years. For example, take the case of the surface protein called VP2. When they looked across all the different rhinovirus serotypes in this group, there was quite a lot of diversity in the gene that makes this protein. They discovered that all the different versions of this gene had a common ancestor sometime around the year 1125. So sometimes your sneezes can be a little bit medieval.

For most people, rhinoviruses are a nuisance, but for some the common cold can have serious consequences. Rhinoviruses can cause acute exacerbations of conditions such as asthma, cystic fibrosis and COPD (chronic obstructive pulmonary disease), so there’s a very real need for a vaccine. Moreover, the economic cost of the common cold has been estimated at an eye-watering $40 billion a year in the US alone in terms of lost work and medical expenses. Even back in World War II, the the common cold had become notorious for its negative impact on the war effort, prompting wary governments to fund post-war programs such as the Common Cold Unit.

Next year will mark 70 years since the first volunteers arrived in Salisbury for their viral holiday, so whatever happened to the common cold vaccine? As it turns out, all those different serotypes weren’t the only problem. Moreover, they might not be as big a barrier as once thought.

Much of the time in the 40s and 50s was spent identifying cold viruses, so it wasn’t until the 60s that vaccine development began in earnest. Researchers were concerned about the increasing number of serotypes, but they had to start somewhere, so early clinical trials began by using a killed version of just one serotype of rhinovirus. The result was underwhelming. They then tried multiple different serotypes at once; still, not much luck. The vaccines just didn’t trigger much of an immune response at all. It’s now thought that this was due in part to an unfortunate catch-22. The techniques used to kill a rhinovirus (so it could be used without causing an infection) were probably damaging many of the protein signatures on the viral surface, the very ones needed for an immune response. It seems that the approach they used to make the rhinovirus vaccine harmless also made it useless.

Why do human rhinoviruses love humans best of all? It has to do with the cells lining your respiratory tract. In order to infect, a rhinovirus must first latch onto a protein called ICAM-1 that sits on the surface of those cells. Mice have ICAM-1, too, but there are enough small differences that human rhinoviruses tend to ignore them. It’s like trying to unlock a different house with the same key. Of course, ICAM-1 was never meant to be a viral access point, even in humans. It’s actually there to help the respiratory tract cells interact with the immune system. But evolution being evolution, human rhinoviruses found a way to use ICAM-1 to their advantage.

A number of researchers are now investigating ways to target ICAM-1 directly and block this viral entry, but it’s a fine line to walk. You want to prevent rhinovirus from latching on yet still allow those normal interactions with the immune system to take place. If you covered your door locks with steel plates, thieves wouldn’t be able to pick the locks, but then you couldn’t use them either.

Curiously, the cotton rat is not new to the study of human viruses. It’s known to be susceptible to a variety of them, including influenza, respiratory syncytial virus (RSV), measles and even polio. But no one knew they also caught our colds.

Then in 2014, another advance was made. It has to do with the fact that rhinoviruses, like all RNA viruses, travel light. They bring little in the way of biological luggage, opting instead to carry a small amount of genetic material. The virus invades the cell and then commandeers the cell’s normal mechanisms to help it make new viruses. As part of this process, the genetic material (RNA) of the rhinovirus provides the instructions to make all the structural proteins it needs to make the viral shell. Instead of these proteins being made one at a time, in the interest of efficiency, one giant protein is made which is then snipped up into individual proteins. This happens in every single serotype.

When a team of researchers in the UK and France examined how these proteins line up back to back in that big precursor protein, they noticed something interesting. Short regions of this big protein are highly similar in almost all of the viruses they examined. Importantly, some of these highly conserved regions are exposed on the viral surface, which means they should be visible to immune cells. One of them included not just VP4, but part of another protein as well — this gave the researchers more to work with than just VP4 alone. It suggested that maybe, just maybe, this snippet of that big protein might work as a vaccine against a wide range of rhinoviruses. So they tried it. They took this region of the protein from one serotype and tested whether it would protect against a different serotype.

It did.

The immunized mice did not get sick, they had no signs of illness at all. There was a clear immune response taking place. The immunized mice produced antibodies to the rhinovirus infection much faster than normal, and they also cleared the virus from their system more rapidly. In vaccinated mice, there was no longer any trace of rhinovirus 4 days after infection. In unvaccinated mice, the virus was still hanging around after 6 days. The findings were published in Plos Pathogens in September, 2014.

So far only a handful of serotypes have been tested and more work is needed to determine whether there is hope of developing a vaccine effective against the many other serotypes in circulation. Nevertheless, it’s a promising proof of concept.

Then, in 1990, the Common Cold Unit closed. They had never found a cure, and a broadly protective vaccine seemed impossible. But it’s now clear that the story is far from over, and we can safely say that they laid the important groundwork for the progress being made today… and that’s nothing to sneeze at.